James D. Acton

Multicenter Evaluation of Infant Lung Function Tests as Cystic Fibrosis Clinical Trial Endpoints

RATIONALE The conducting of clinical trials in infants with cystic fibrosis (CF) has been hindered by lack of sensitive outcome measures. OBJECTIVES To evaluate safety, feasibility, and ability to detect abnormalities in lung function of serial pulmonary function tests (PFTs) in infants with CF. METHODS Multicenter observational study using a commercial device, rigorous training, ongoing quality control, and over-reading of data by an independent panel. Raised volume rapid thoracoabdominal compression technique and plethysmography were performed at enrollment and at 6 and 12 months, with an additional 1-month reproducibility visit. MEASUREMENTS AND MAIN RESULTS A total of 342 procedures were performed in 100 infants with CF at 10 centers. FRC measurements were acceptable at a higher proportion of study visits (89%) than raised volume (72%) or fractional lung volume (68%) measurements. Average Z scores for many parameters differed significantly from historical control values. Mean (95% confidence interval) Z scores were: -0.52 (-0.78 to -0.25) for forced expiratory flow at 75% (FEF₇₅) for FVC; 1.92 (1.39-2.45) for FRC; 1.22 (0.68-1.76) for residual volume; 0.87 (0.60-1.13) for FRC/total lung capacity; and 0.66 (0.27-1.06) for residual volume/total lung capacity. For future multicenter clinical trials using infant PFTs as primary endpoints, minimum detectable treatment effects are presented for several sample sizes. CONCLUSIONS In this 10-center study, key PFT measures were significantly different in infants with CF than in historical control subjects. However, infant PFTs do not yet appear ready as primary efficacy endpoints for multicenter clinical trials, particularly at inexperienced sites, based on acceptability rates, variability, and potentially large sample sizes required to detect reasonable treatment effects.

Randomized Clinical Trial of Behavioral and Nutrition Treatment to Improve Energy Intake and Growth in Toddlers and Preschoolers With Cystic Fibrosis

Objective. To conduct a randomized clinical trial comparing a behavioral and nutrition intervention (BEH) with a usual care control condition (CTL) for children (ages 18 months to 4 years) with cystic fibrosis (CF) and pancreatic insufficiency. This trial was designed to (1) evaluate a randomized comparison of BEH with CTL over 8 weeks, (2) provide a replication of the impact of BEH by inviting the CTL group to receive BEH after 8 weeks, and (3) examine the maintenance of BEH at 3- and 12-month follow-up. Methods. Of 14 eligible children, 10 were randomly assigned and initiated treatment (71% recruitment rate). Four participants were randomly assigned to BEH, and 6 were assigned to CTL (5 of whom chose to crossover to BEH). BEH included nutrition counseling to increase energy intake (via types of foods and addables/spreadables) and child behavioral management training to teach parents differential attention and contingency management skills. CTL was consistent with the 2002 CF Foundation Consensus Conference Guidelines for nutritional care. Results. BEH led to greater increases in energy intake pre- to posttreatment than CTL as measured by calories per day (842 kcal/day vs −131 kcal/day change). On receiving BEH, the change in energy intake was replicated with the CTL group (892 kcal/day change). At 3- and 12-month follow-up, energy intake was maintained (672 kcal/day increase from baseline and 750 kcal/day increase from baseline, respectively). Children in this study met or exceeded normal weight and height velocities from pretreatment to the 3-month follow-up (mean weight: 1.4 kg/6 months; mean height: 5.1 cm/6 months) and from posttreatment to the 12-month follow-up (mean weight: 2.5 kg/12 months; mean height: 8.3 cm/12 months). Conclusions. Toddlers and preschoolers who have CF and received BEH were able to meet the energy intake recommendations for this disease and maintain these gains up to 12 months after treatment. In addition, these children demonstrated weight and height velocities from pretreatment to 12-month follow-up, consistent with the goal of normal growth. BEH is a promising, evidence-based, early nutritional intervention for children with CF. An upcoming multisite clinical trial will test BEH versus an attention control condition using a larger sample (N = 100), providing additional evidence about the efficacy of this treatment for energy intake and growth in young children with CF.

Improvements in lung function outcomes in children with cystic fibrosis are associated with better nutrition, fewer chronic pseudomonas aeruginosa infections, and dornase alfa use.

OBJECTIVE To compare lung function and nutritional outcomes in cystic fibrosis (CF) for 2 birth cohorts in our CF center. STUDY DESIGN Patients with CF born between 1985 and 2000 treated in our CF center before age 5 years were included. The patients were divided into 2 equal birth cohorts for comparison: birth cohort 1 (born between 1985 and 1992) and birth cohort 2 (born between 1993 and 2000). To compare lung function, we used forced expiratory volume in the first second (FEV(1))% predicted and FEV(1)% predicted slope from age 6 to 12 years. We hypothesized that we would find significant improvements in lung function and nutritional outcomes in our patients with CF. RESULTS The patients born between 1993 and 2000 (birth cohort 2) had better lung function, a slower rate of decline in lung function, and better nutritional outcomes compared with those born between 1985 and 1992 (birth cohort 1). Factors associated with a slower rate of decline in lung function in both groups were a higher baseline body mass index (BMI)%, a slower BMI% rate of decline, absence of chronic Pseudomonas aeruginosa respiratory infection, and initiation of dornase alfa (Pulmozyme) therapy before age 9 years. CONCLUSION Our results demonstrate dramatically improved lung function and nutritional outcomes in the children with CF in our center. The improvements in lung function outcomes are associated with better nutrition, fewer chronic P aeruginosa infections, and dornase alfa therapy.

Relations between depressive and anxious symptoms and quality of life in caregivers of children with cystic fibrosis

Little is known about depressive and anxious symptoms and quality of life (QOL) in caregivers of children with cystic fibrosis (CF). The aims of this study were to: (1) assess rates of female and male caregiver depressive and anxious symptoms, and (2) evaluate relations between depressive and anxious symptoms, caregiver QOL, and health outcomes.

Screening for symptoms of depression and anxiety in adolescents and young adults with cystic fibrosis.

Although studies have assessed symptoms of depression and anxiety in individuals with cystic fibrosis (CF), few have been conducted since the advent of new medical treatments (e.g., nebulized antibiotics, ThAIRpy Vest). Study objectives were to: (1) document symptoms of depression and anxiety for adolescents and young adults with CF and compare with normative values, (2) examine the associations among depressive/anxiety symptoms and gender, age, lung function, and body mass index, and (3) determine the relations between adolescent and caregiver symptoms of depression and anxiety.

Improving Evidence-Based Care in Cystic Fibrosis Through Quality Improvement

OBJECTIVE To increase clinician adherence to prescribing guidelines for pulmonary medications in children with cystic fibrosis (CF). DESIGN Quality improvement project with multiple time series design. SETTING The CF center at a tertiary care pediatric hospital in the United States. PATIENTS Children with CF who were eligible to receive oral azithromycin, nebulized dornase alfa, or inhaled tobramycin sulfate based on prescribing guidelines for CF lung disease. INTERVENTION Evidence-based prescribing guidelines were designed by a local committee to reflect consensus recommendations from the CF Foundation. Clinicians and families were educated about guidelines. Adherence to prescribing guidelines was tracked using a local CF database and record reviews. Weekly meetings were used to highlight adherence failures and promote clinician accountability. MAIN OUTCOME MEASURE The rate of clinician adherence to prescribing guidelines. RESULTS One hundred seventy patients with CF were included. At the start of the project, the rate of clinician adherence to prescribing guidelines was 62%. After 3 months of the project, the rate of clinician adherence to prescribing guidelines was 87% (odds ratio = 4.6; 95% confidence interval, 3.0-7.0). The improvements in adherence to prescribing guidelines were sustained for 21 months of follow-up. CONCLUSIONS Educating clinicians about prescribing guidelines, sharing guidelines with families, and monitoring clinician adherence improve prescribing adherence to evidence-based recommendations.

Behavioral and nutritional treatment for preschool-aged children with cystic fibrosis a randomized clinical trial

IMPORTANCE Evidence-based treatments that achieve optimal energy intake and improve growth in preschool-aged children with cystic fibrosis (CF) are a critical need. OBJECTIVE To test whether behavioral and nutritional treatment (intervention) was superior to an education and attention control treatment in increasing energy intake, weight z (WAZ) score, and height z (HAZ) score. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial included 78 children aged 2 to 6 years (mean age, 3.8 years) with CF and pancreatic insufficiency (intervention, n = 36 and control, n = 42). The study was conducted at 7 CF centers between January 2006 and November 2012; all 78 participants who met intent-to-treat criteria completed through follow-up. INTERVENTIONS Behavioral intervention combined individualized nutritional counseling targeting increased energy intake and training in behavioral child management skills. The control arm provided education and served as a behavioral placebo controlling for attention and contact frequency. Both treatments were delivered in person or telehealth (via telephone). Sessions occurred weekly for 8 weeks then monthly for 4 months (6 months). Participants then returned to standard care for 1 year, with 12-month follow-up thereafter. MAIN OUTCOMES AND MEASURES Changes in energy intake and WAZ score were examined from pretreatment to posttreatment (6 months) and change in HAZ score was assessed pretreatment to follow-up (18 months). Covariates included sex, Pseudomonas aeruginosa status at baseline, and treatment modality (in person vs telehealth). RESULTS At baseline, mean (SD) energy intake was 1462 (329) kcals/d, WAZ score was -0.44 (0.81), and HAZ score was -0.55 (0.84). From pretreatment to posttreatment, the intervention increased daily energy intake by 485 calories vs 58 calories for the control group (adjusted difference, 431 calories; 95% CI, 282 to 581; P < .001) and increased the WAZ score by 0.12 units vs 0.06 for the control (adjusted difference, 0.09; 95% CI, -0.06 to 0.24; P = .25). From pretreatment to follow-up, the intervention increased the HAZ score by 0.09 units vs -0.02 for the control (adjusted difference, 0.14 units; 95% CI, 0.001 to 0.27; P = .049). Measured treatment integrity and credibility were high for both groups. CONCLUSIONS AND RELEVANCE Behavioral and nutritional intervention improved energy intake and HAZ score outcomes but not WAZ score outcomes. Our results provide evidence that behavioral and nutritional treatment may be efficacious as a nutritional intervention for preschoolers aged 2 to 6 years with CF and pancreatic insufficiency. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT00241969.

Association of lung function, chest radiographs and clinical features in infants with cystic fibrosis

The optimal strategy for monitoring cystic fibrosis lung disease in infancy remains unclear. Our objective was to describe longitudinal associations between infant pulmonary function tests, chest radiograph scores and other characteristics. Cystic fibrosis patients aged ≤24 months were enrolled in a 10-centre study evaluating infant pulmonary function tests four times over a year. Chest radiographs ∼1 year apart were scored using the Wisconsin and Brasfield systems. Associations of infant pulmonary function tests with clinical characteristics were evaluated with mixed effects models. The 100 participants contributed 246 acceptable flow/volume (forced expiratory volume in 0.5 s (FEV0.5) and forced expiratory flow at 75% of the forced vital capacity (FEF75%)), 303 functional residual capacity measurements and 171 chest radiographs. Both Brasfield and Wisconsin chest radiograph scores worsened significantly over the 1-year interval. Worse Wisconsin chest radiograph scores and Staphylococcus aureus were both associated with hyperinflation (significantly increased functional residual capacity), but not with diminished FEV0.5 or FEF75%. Parent-reported cough was associated with significantly diminished forced expiratory flow at 75% but not with hyperinflation. In this infant cohort in whom we previously reported worsening in average lung function, chest radiograph scores also worsened over a year. The significant associations detected between both Wisconsin chest radiograph score and S. aureus and hyperinflation, as well as between cough and diminished flows, reinforce the ability of infant pulmonary function tests and chest radiographs to detect early cystic fibrosis lung disease. Infant pulmonary function tests and chest radiographs are able to detect early cystic fibrosis lung disease http://ow.ly/pv7pt

Is an FEV1 of 80% predicted a normal spirometry in cystic fibrosis children and adults?

FEV1 is considered the gold standard spirometric measure for the assessment and management of cystic fibrosis lung disease. Recent evidence suggests that tests at lower lung volumes may be more sensitive.

315 Two-year outcomes of behavior and nutrition treatment for young children with Cystic Fibrosis

Aims: To evaluate whether changes in energy intake and growth velocity due to behavior and nutrition treatment (BEH) for young children with CF were maintained at 2-yr follow-up (f-up). Methods: Two-yr f-up data for 9 subjects who completed an 8-week BEH intervention, which included nutrition counseling and parental child behavior management training. For f-up assessments three 24-hour recall diet diaries and height (ht) & weight (wt) were obtained. Average daily energy intake and growth velocity (ht&wt) were outcome variables. Velocity was benchmarked against expected velocities for a same age child without CF at the 50th percentile (US 2000 Center for Disease Control growth charts). Results: The average daily energy intake was 2,589±519 kcal/day at the 2-yr f-up. This compares favorably to data from post-treatment (2151±301 kcal/day). Pretreatment intake was 1,381±198kcal/day. Subjects exceeded the goal of 120% RDA/day for energy intake at 2-yr f-up. The average wt velocity was 4.94/2-yr (Median: 4.6). Seven of 9 subjects were above benchmark. The average ht velocity was 15.8/2-yr (Median: 15.7). All subjects were above benchmark. Conclusions: Upon returning to standard care, young children with CF who received BEH continue to maintain clinically significant increases in energy intake, and demonstrate patterns of normal growth at 2-yr post-treatment. Findings suggest this intervention is durable and families are able to continue to implement skills and knowledge acquired during treatment. Supported by US National Institutes of Health. 8. Nutrition